Recent work from our laboratory shows that in mice a subset of the olfactory sensory neurons (OSNs) that express the transient receptor potential channel M5 (TRPM5) respond to semiochemicals (chemicals involved in animal communication, from the Greek semeion for ``sign'') including putative pheromones, peptides from the major histocompatibility complex (MHC) and urine (2). Therefore, the response to putative pheromones and other semiochemicals is not mediated exclusively by the vomeronasal organ. In this grant we will test the hypothesis that this subset of OSNs expressing TRPM5 respond to semiochemicals using a specific subset of olfactory receptors. Importantly, despite the fact that humans do not appear to express a vomeronasal organ, data suggest that they respond to putative pheromones and other semiochemicals (4, 5). Therefore we will perform experiments searching for responses to semiochemicals in mice and humans. Using strong techniques involving recording from single OSNs, evaluation of olfactory receptor expression in these neurons using RNA-Seq, and recording responses of specific olfactory receptors to large numbers of semiochemicals and odorants we propose three specific aims: Aim 1. Test the hypothesis that olfactory receptors in mouse TRPM5+ OSNs are differentially expressed in the two genders. Aim 2. Are TRPM5+ OSNs involved in responses to semiochemicals at low concentrations in both human and mouse? Aim 3. Test the hypothesis that olfactory receptors expressed in TRPM5-expressing OSNs respond to semiochemicals at low concentrations. RELEVANCE: This grant will examine olfactory sensory neurons from the main olfactory epithelium of mice and humans to identify olfactory receptors that respond to semiochemicals including putative pheromones, major histocompatibility complex peptides and liquids released from the body. This study is particularly relevant to understand human chemoreception, as humans do not have a functional vomeronasal organ and may utilize the main olfactory system for detection of semiochemicals (5, 8). Identifying volatile molecules that can manipulate the hormonal system of humans would be an important non-invasive method for control of human health. Our studies will provide novel information on olfactory receptors mediating semiochemical sensing in the main olfactory system.